Immunogenicity In the past year we have succeeded in identifying all the major B cell epitopes recognized by the mouse immune system and have made a new immunotoxin HA22-LR-8M that is fully active and does not induce antibodies when injected i.v. into mice. We are now trying to identify the human specific B cell epitopes. We have also initiated a program to identify and remove human specific T cell epitopes. We have used information gained in the HA22 studies to improve the immunotoxin SS1P directed at mesotheliomas. We have made a new immunotoxin SS1-LR-GGS-8M that has very low immunogenicity yet retains high cytotoxic activity. We have studied the mechanism of mesothelin shedding and identified the major enzyme involved in the shedding process. Inhibition of this enzyme could increase the activity of immunotoxins. In collaboration with D. FitzGerald we have begun to study how protein synthesis arrest leads to apoptosis and identified BAK and Mcl-1 as critical players in this process. In collaboration with Alan Wayne POB, we have analyzed the response of cells directly isolated from patients with ALL to HA22 killing and set up an assay that may help predict if patients will respond to treatment. We have also isolated HA22 resistant cell lines and are using these to understand the basis of clinical drug resistance.